Novel translatable optical imaging platform for staging vascular impairment in Alzheimer's disease Project summary/abstract A challenge in studying and treating Alzheimer's disease (AD) is cost-effective quantitative imaging. Current imaging strategies focus on identifying amyloid-beta (A2) plaques, the defining lesion in AD, and are expensive and hard to use. Even so, plaques alone have been shown to not be specific for clinical dementia, and evidence is building for cerebrovascular risk factors and impairments downstream of A2 pathology. The critical question is whether a set progression of vascular impairments are caused by and likely exacerbate A2 pathology leading ultimately to cell death and memory loss. If so, an alternate strategy of imaging for specific vascular impairments and cellular hypometabolism may supplement current imaging modalities in the study and management of AD. The objective for this fellowship proposal is to apply and develop a novel in vivo non- contact spectroscopy mapping technique called spatial frequency domain imaging (SFDI) with these aims: 1) To use SFDI to sequence specific vascular impairments in triple transgenic AD mice in vivo. 2) To correlate cellular hypometabolism to levels of vascular impairment. This project will exploit SFDI's unique ability to intrinsically resolve both neurovascular physiology as well as brain structural alterations. The results could increase basic science understanding of AD, suggest therapies, and translate to prognosis and monitoring of AD in the clinic, directly addressing the goals of the NIA at the NIH. Several features render this project particularly suitable for the F30 mechanism. SFDI, capable of assaying metabolism, microvascular function, and tissue composition changes in the brain was developed by the trainee's sponsor Dr. Bruce Tromberg, who also directs the Beckman Laser Institute and Medical Clinic, a state-of-the-art biomedical optics imaging facility with new translational instruments constantly being developed. Several of these technologies will be used and further developed by the trainee under Dr. Tromberg's guidance. The proposed animal experiments are done in collaboration with the UCI Institute for Memory Impairment and Neurological Disorders led by Dr. Frank LaFerla, famous for developing the first mouse model expressing AD-specific pathology, namely extracellular amyloid plaques and intracellular hyper- phosphorylated tau. Learning and communicating the concepts/techniques from engineering and animal work will lay the foundation for incorporating similar interdisciplinary components in the trainee's future research endeavors. Thus, the development of SFDI for alternative, non-invasive testing strategies for AD is likely to equip the trainee with technical imaging and neuroscience experience, in addition to greatly improving knowledge of early vascular impairment in AD. PUBLIC HEALTH RELEVANCE: More than 35 million people world-wide have Alzheimer's disease (AD) 33, but prevention, early detection, and quantitative monitoring of disease progression is limited. Understanding the progression of vascular impairment in the pathogenesis of AD will suggest treatment, prognosis and monitoring strategies for AD. Furthermore, analogous tissue spectroscopy techniques and optical biomarkers advanced by this project can directly translate into human trials and, eventually, the clinic relatively easily and cost-effectively.